It has been said that hyperlipidemia, diabetes, hypertension or the like is one of the risk factors for arteriosclerosis. Hyperlipidemia is a condition where the concentration of lipid such as cholesterol is abnormally elevated in the blood. Types of hyperlipidemia, depending on the cause, include primary hyperlipidemia caused by genetic abnormality in enzyme, protein, lipoprotein and the like which participate in the metabolism of low-density lipoprotein (LDL), secondary hyperlipidemia due to various disease or drug administration, and acquired hyperlipidemia basically resulting from overnutrition.
Meanwhile, lipid taken in from food is absorbed in the small intestine by the action of bile acid, and secreted as chylomicron in the blood via lymphatic vessels. The triglyceride (TG) moiety of the secreted chylomicrons is hydrolyzed to free fatty acids by the action of lipoprotein lipase (LPL) existing in capillary vessels to become chylomicron remnants having a high content of cholesteryl ester (CE), which is then absorbed in the liver by the mediation of chylomicron remnant receptor in the liver. Further, in the liver, the absorbed chylomicron remnant and free fatty acids are converted to CE and TG, respectively, which are then associated with apolipoprotein B synthesized on rough surfaced endoplasmic reticulum to form very low density lipoprotein (VLDL). The VLDL is transferred to the Golgi apparatus, modified and secreted outside cells, and it becomes intermediate density lipoprotein (IDL) by the action of LPL. The IDL is converted to LDL by the action of hepatic triglyceride lipase (HTGL), and lipids are distributed to peripheral tissues.
It has long been indicated that, during the above-mentioned formation of chylomicron in the small intestine or VLDL in the liver, a protein having TG- or CE-transfer activity is existing in microsomal fractions of the small intestine or liver. Meanwhile, the protein, i.e. MTP (microsomal triglyceride transfer protein: hereinafter also abbreviated as MTP) was purified and separated from microsomal fractions of bovine liver by Wetterau et al. in 1985 (Wetterau J. R. et al: Chem. Phys. Lipids 38, 205-222 (1985)). MTP, however, began attracting a lot of attention in the field of clinical medicine only after it was reported in 1993 that the cause of abetalipoproteinemia lay in the deficit of MTP. In other word, the disease is characterized in that, while the genes related to apolipoprotein B are normal, apolipoprotein B is hardly detected in the serum, the level of serum cholesterol is 50 mg/dL or lower, the level of serum triglyceride is extremely low. By this finding, it has been shown that MTP is an integral protein involved in the association between apolipoprotein B and TG or CE, i.e. the formation of VLDL or chylomicron, and plays an essential role in secretion thereof. Accordingly, it was thought that MTP inhibitors can become to be an excellent anti-hyperlipidemic agent which can inhibit the production of lipoproteins such as chylomicron, VLDL, and the like. In addition, by inhibiting MTP in the small intestine and thus suppressing the production of chylomicron, it may be expected that excess absorption of triglycerides responsible for hyperliplidemia is inhibited, leading to creation of a new type of anti-hyperlipidemic agents.
Since lipid is by nature insoluble in water, lipid in the blood is combined with a hydrophilic protein known as apolipoprotein and exists as so-called lipoprotein. All the VLDL, IDL, LDL or chylomicron, etc. related to hyperlipidemia are a lipoprotein.
MTP exists in the microsome fractions of hepatocytes and intestinal epithelial cells, and catalyses the transfer of TG or CE in cells. In the liver and small intestine, along with the synthesis of apolipoprotein B (apolipoprotein B100 in the liver and apolipoprotein B48 in the small intestine), TG and CE are combined with respective apolipoprotein B by the transfer activity of MTP, and thus VLDL or chylomicron is formed. As a result, those lipoproteins are secreted outside the cells as VLDL in the liver or as chylomicron in the small intestine. It should be said that MTP is indispensable for the construction of those lipoproteins. Namely, if the activity of MTP is blocked, the transfer of lipid such as TG and CE, etc. to apolipoprotein is inhibited, whereby formation of a lipoprotein can be inhibited.
On the other hand, it has been elucidated that LDL in general is closely related to the progression of arteriosclerosis. That is, LDL permeating endothelium of blood vessels is deposited in intercellular matrix of vessel wall, where oxidative denaturation takes place and lipid peroxides or denaturated proteins induce a series of inflammation reactions. Consequently, macrophage emigration in blood vessels leading to lipid deposit or composition of layers of foamy cells, migration or proliferation of smooth muscle cells and increase in intercellular matrix, etc. take place, which leads to the development of arteriosclerosis plaque. On the basis of the above, it is supposed to be possible to prevent or treat arteriosclerosis, coronary artery diseases or hypertension by reducing the level of LDL.
As already mentioned, it is possible to inhibit the formation of lipoprotein such as chylomicron, VLDL, LDL, etc. by inhibiting the action of MTP. Accordingly, it has been expected that it should become possible to control TG, cholesterol and lipoproteins such as LDL, etc. in blood and to control lipid in cells by adjusting the activity of MTP, and therefore, a novel agent for the treatment or prophylaxis of hyperlipidemia, arteriosclerosis, coronary artery diseases, diabetes, obesity, or hypertension, and further, an agent for the treatment or prophylaxis of pancreatitis, hypercholesterolemia, hyperglyceridemia, etc. has been expected to be provided.
However, with the development of MTP inhibitors, some cases of fatty liver were reported and concern over hepatotoxicity has been raised (M. Shiomi and T. Ito, European Journal of Pharmacology 431, p. 127-131 (2001)). This is presumably because even if a compound exerts inhibitory activity against MTP in the small intestine, it is absorbed from the intestine and the like, and remains in the blood or liver, which results in also inhibiting MTP in the liver.
In the conventional manners, combined therapies of various combinations of different antihyperlipidemic drugs have been tried. However, when, for example, a statin-type drug and a resin-type drug are given together, undesirable side effects such as elevated GOT and GPT, constipation, blocking of absorption of vitamins A, D, E and K and the like are observed. On the other hand, when a statin-type drug and a fibrate drug are given together, side effects such as rhabdomyolysis or elevated CPK (creative phosphokinase) are observed. Thus, with regard to a combined therapy for hyperlipidemia, a medicament for a combined administration which can be administered in combination with a conventional antihyperlipidemic drug without causing any above-mentioned side effect has been desired.
Meanwhile, examples of the known compound having MTP inhibitory activity are described below.
The following compound is disclosed in WO97/26240.

The following compound is disclosed in WO97/43257.

The following compound is disclosed in WO98/23593.
(In the formula, G is phenyl, heterocyclyl, —CH2CN, diphenylmethyl, C2-C12 alkyl, C2-C12 perfluoroalkyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, —(CH2)n—COOH, —(CH2)n—COO-alkyl, etc.)
The following compound is disclosed in WO99/63929.

The following compound is disclosed in WO2000/5201.

The following compound is disclosed in J. Med. Chem. (2001), 44(6) p. 851-856.

The following compound is disclosed in EP 1099701.

The following compound is disclosed in WO2001/77077.

The following compound is disclosed in J. Med. Chem. (2001), 44 (6) p. 4677-4687.

The following compound is disclosed in WO2002/4403.

In the above literatures, however, there is no disclosure of a compound comprising ester as the essential structure, much less the disclosure or suggestion of the data indicating that the disclosed compound selectively inhibits MTP in the small intestine while rarely affects MTP in the liver.
Further, WO2002/28835 discloses the following compound represented by the formula:
wherein
L is an unsaturated 3- to 10-membered heterocycle which may be substituted by a suitable substituent,Y is -(A1)m-(A2)n-(A4)k-[in the formula, A1 is lower alkylene or lower alkenylene and these two groups may be substituted by a suitable substituent; A2 is —N(R3)—, —CO—N(R3)—, —NH—CO—NH—, —CO—O—, —O—, —O—(CH2)2—N(R3)—, —S—, —SO—, or —SO2—(in the formula, R3 is hydrogen or a suitable substituent); A4 is lower alkylene, lower alkenylene or lower alkynylene; and k, m and n are each independently 0 or 1].
However, the compound disclosed in this patent differs from the compound of the present invention in its structure with respect to the moiety of —Y-L-. Further, in this patent, there is no disclosure or suggestion of the data indicating that the disclosed compound selectively inhibits MTP in the small intestine while rarely affects MTP in the liver.
Furthermore, WO2003/72532 discloses the following compound having selective inhibition of MTP in the small intestine, represented by the formula:
wherein Alk2 is alkanediyl or alkenediyl;
m is 0 or an integer of 1 to 3;
D is C1-C6 alkyl, C2-C6 alkenyl, C2-C7 alkoxycarbonyl, —N(R42)—CO(R43) (wherein R42 is hydrogen or C1-C6 alkyl, and R43 is C6-C14 aryl or C7-C16 aralkyl), or
wherein R5, R6 and R7 are each independently C1-C6 alkyl, C1-C6 alkoxy, C2-C7 alkoxycarbonyl, carboxyl, halogen, cyano, nitro, halo C1-C6 alkyl, C1-C6 acyl, hydroxy, amino, optionally substituted C6-C14 aryl or —(CH2)r—CON(R16)(R17) (wherein R16 and R17 are each independently hydrogen, C1-C6 alkyl or halo C1-C6 alkyl, and r is 0 or an integer of 1 to 3); ring C is C6-C14 aryl, C7-C15 arylcarbonylamino, C8-C17 aralkylcarbonylamino, heterocyclic residue, C3-C7 cycloalkyl, or C7-C16 aralkyl, or ring C taken together with R7 and R8 may form a group of the formula:

R8 and R9 are each independently hydrogen, C1-C6 alkyl, optionally substituted C6-C14 aryl, hydroxy-C1-C6 alkyl, —CON(R18)(R19) (wherein R18 and R19 are each the same or different, and are hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, halo-C1-C6 alkyl, C2-C12 alkoxyalkyl or optionally substituted C6-C14 aryl), —COO(R20) or (CH2)s—OCOR(R20) (wherein R20 is hydrogen, C1-C6 alkyl or C3-C7 cycloalkyl, and s is 0 or an integer of 1 to 3), —N(R21)(R22) (wherein R21 and R22 are each the same or different, and are hydrogen, C1-C6 alkyl, C1-C6 acyl or C1-C6 alkylsulfonyl, or R21 and R22 together with the nitrogen atom to which they are attached may form a group of the formula:
or R8 and R9 taken together may form C3-C7 cycloalkyl.
However, the compound disclosed in this patent literature differs from the compound of the present invention in its chemical structure with respect to the moiety of -(Alk2)m-CR8R9—.
In addition, WO2005/21486 discloses the following compound of the formula:
wherein R1 and R2 are each the same or different, and are hydrogen, C1-C6 alkyl, C3-C7 cycloalkyl, C1-C6 alkoxy, halo C1-C6 alkyl, halo C1-C6 alkyloxy, optionally substituted C6-C14 aryl, optionally substituted C7-C16 aralkyl, optionally substituted C6-C14 aryloxy, optionally substituted C7-C16 aralkyloxy, optionally substituted C7-C15 arylcarbonyl, optionally substituted heterocyclic ring, C2-C7 alkoxycarbonyl, halogen, C2-C6 alkenyl, C1-C6 acyl, cyano, —N(R40)(R41) (wherein R40 and R41 are each the same or different, and are hydrogen, C1-C6 alkyl or optionally substituted C6-C14 aryl) or —(CH2)r—O—CO—R100 (wherein R100 is C1-C6 alkyl, C1-C6 alkoxy or C2-C12 alkoxyalkyl, and r is 0 or an integer of 1 to 3) ;
ring A is C6-C14 aryl, heterocyclic ring,

X is —COO—(CH2)n—, —CON)(R10)—(CH2)n— or —N(R10)—CO—(CH2)n— (wherein R10 is hydrogen, C1-C6 alkyl or C3-C8 cycloalkyl, and n is 0 or an integer of 1 to 3) ;
R3, R4 and R200 are each the same or different, and are hydrogen, hydroxy, halogen, optionally substituted C1-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl, C7-C16 aralkyloxy, C1-C6 acyl, C3-C10 alkoxycarbonylalkyl, optionally substituted heterocyclic ring, —CON(R11)(R12) [wherein R11 and R12 are each the same or different, and are hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C6-C14 aryl, optionally substituted C7-C16 aralkyl or C1-C6 alkoxy, or R11 and R12 together with the nitrogen atom to which they are attached may form a group of the formula:
(wherein R0 is hydrogen, hydroxy, C1-C6 alkyl or C1-C6 acyl, and p is 0 or an integer of 1 or 2)], —(CH2)q′—N(R13)(R14) [wherein R13 and R14 are each the same or different, and are hydrogen, C1-C6 alkyl, C2-C7 alkoxycarbonyl or C1-C6 acyl, or R13 and R14 together with the nitrogen atom to which they are attached may form a group of the formula:
(wherein p has the same meaning as defined above), and q′ is 0 or an integer of 1 to 3], —CO(R15) [wherein R15 is hydroxy, C1-C6 alkyl, C1-C6 alkoxy, optionally substituted C6-C14 aryloxy or C7-C16 aralkyloxy], or —(CH2)r′—O—CO—R100′ [wherein R100′ is C1-C6 alkyl, C1-C6 alkoxy, C2-C12 alkoxyalkyl or —N(R40)(R41)(R40 and R41 have the same meanings as defined above), and r′ is 0 or an integer of 1 to 3];
ring B is
(wherein k is 0 or an integer of 1 or 2), or the nitrogen atom to which R10 is attached, taken together with R3, R10 and ring B, may form a group of the formula:
(wherein R300 is optionally substituted C1-C6 alkyl);
Alk1 is alkanediyl or alkenediyl;
Alk2 is alkanediyl or alkenediyl;
l is 0 or an integer of 1 to 3;
m is 0 or an integer of 1 to 3;
ring C is
(q is 0 or an integer of 1 to 4);
R5, R6 and R7 are each the same or different, and are hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C2-C7 alkoxycarbonyl, carboxyl, halogen, cyano, nitro, halo C1-C6 alkyl, C1-C6 acyl, hydroxy, amino, optionally substituted C6-C14 aryl, —(CH2)r—CON(R16)(R17) (wherein R16 and R17 are each the same or different, and are hydrogen, C1-C6 alkyl or halo C1-C6 alkyl, and r is 0 or an integer of 1 to 3) or —(CH2)r″—O—CO—R100″ (wherein R100″ is C1-C6 alkyl, C1-C6 alkoxy or C2-C12 alkoxyalkyl, and r″ is 0 or an integer of 1 to 3);
R8 and R9 are each the same or different, and are hydrogen, optionally substituted C1-C6 alkyl or optionally substituted C6-C14 aryl;
E is —O— or —N(R90)— (wherein R90 is hydrogen or C1-C6 alkyl);
Y is —O—CO—O—, —O—CO—, —CO—O—, —CO—O—C)(R110)(R111)—O—CO—, —CO—O—C(R110)(R111)—O—CO—O—, —O—CO—O—, —O—CO—O—C(R111)(R111)—O—CO—, —O—CO—C(R110)(R111)—O—, —O—CO—C)(R110)(R111)—C(R110)(R111)—O—, or —O—C)(R110)(R111)—CO—O— (wherein R110 and R111 are each the same or different, and are hydrogen or C1-C6 alkyl; provided that when Y is —CO—O—, then R3 is —(CH2)r′—O—CO—R100′ (R100′ and r′ have the same meanings as defined above).
However, the compound disclosed in this patent literature differs from the compound of the present invention in its chemical structure.
